5-Alkanoyl-6-alkyl-2(1H)-pyridinones, their preparation and their cardiotonic use

ABSTRACT

4-R 2  -5-(Lower-alkanoyl)-6-(lower-alkyl)-2(1H)-pyridinones (I), useful as cardiotonics, where R 2  is hydrogen or methyl, are prepared by reacting 2-(lower-alkanoyl)-1-(lower-alkyl)ethenamine (II) with lower-alkyl 2-propynoate or 2-butynoate respectively or by hydrolyzing 4-R 2  -5-(lower-alkanoyl)-6-(lower-alkyl)-1,2-dihydro-2-oxonicotinonitrile (III), Q is CN) or corresponding 4-R 2  -5-(lower-alkanoyl)-6-(lower-alkyl)-1,2-dihydro-2-oxonicotinamide to produce the corresponding 5-(lower-alkanoyl)-6-(lower-alkyl)-1,2-dihydro-2-oxonicotinic acid and decarboxylating said substituted nictotinic acid to produce I. Also disclosed and claimed are cardiotonic uses of 3-Q-4-R 2  -5-(lower-alkanoyl)-6-(lower-alkyl)-2(1H)-pyridinones where Q is hydrogen or cyano and R 2  is hydrogen or methyl (III). Also shown and claimed is methyl 4-acetyl-5-amino-2,4-hexadienoate or acid-addition salt thereof, useful as intermediate or cardiotonic.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation-in-part of copending application Ser.No. 357,872, filed Mar. 15, 1982 and now U.S. Pat. No. 4,412,077 issuedOct. 25, 1983.

BACKGROUND OF THE INVENTION

(a) Field of the Invention

This invention relates to alkanoylpyridinones, their preparation andtheir use as cardiotonics.

(b) Description of the Prior Art

Sunthankar et al. [Indian J. of Chemistry 11, 1315-16 (1973)] show thereaction of cyanoacetamide with conjugated enol ethers, such asethoxymethylenemalonate and analogous conjugated enol ethers to producevarious substituted 2-pyridinones including5-acetyl-1,2-dihydro-6-methyl-2-oxo-3-pyridinecarbonitrile and5-acetyl-1,2-dihydro-6-methyl-2-oxo-3-pyridinecarboxamide. No utility isshown for these compounds.

Kato et al. [J. Heterocyclic Chem. 18, 603-606 (1981)] show, inter alia,the dehydrogenation of 5-acetyl-3,4-dihydro-6-methyl-2(1H)-pyridinone byheating it with palladium black to produce5-acetyl-6-methyl-2(1H)-pyridinone, which in turn is reacted withphosphorus oxychloride (phosphoryl chloride) to produce a mixture of6-chloro-3-ethynyl-2-methylpyridine and6-chloro-3-(1-chlorovinyl)-2-methylpyridine.

Kato et al. [Chem. Pharm. Bull. 17, 2411-2416 (1969)] disclose thepreparation of 5-acetyl-3,4-dihydro-6-methyl-2(1H)-pyridinone in twoways: (a) by refluxing 4-oxo-2-penten-2-amine and acrylic anhydride inchloroform (75% yield); and (b) by heating 4-oxo-2-penten-2-amine andethyl acrylate in ethanol containing sodium ethoxide (9% yield).

Example 13 of U.S. Pat. No. 3,654,291, issued April 4, 1972, shows thereaction of 3-cyano-6-methyl-2(1H)-pyridinone with methylmagnesiumiodide in benzene to produce 3-acetyl-6-methyl-2(1H)-pyridinone, whichis then used as an intermediate to prepare the corresponding3-acetyl-6-methyl-5-nitro-2(1H)-pyridinone, in turn, an intermediate forpreparing the corresponding 5-amino compound, also used as anintermediate.

Fujita [Chem. Pharm. Bull. 23, 501-506 (1975)] in a chemical paperreporting the results of acylation of 1-alkyl-2(1H)-pyridinones byvarious means shows the preparation of various 5-acyl- and3,5-diacyl-1-alkyl-2(1H)-pyridinones, including5-acetyl-1-methyl-2(1H)-pyridinone and its 5-(RCO) homologs where R isC₂ H₅, C₃ H₇ and C₄ H₉. No pharmaceutical properties of these compoundsare disclosed.

Krasnaya et al [C.A. 87, 68099r (1977)] show, inter alia, the use ofderivatives of ethyl 2-acetyl-5-amino-2,4-pentadienoate as anintermediate.

SUMMARY OF THE INVENTION

In a composition of matter aspect, the invention resides in 4-R₂-5-(lower-alkanoyl)-6-(lower-alkyl)-2(1H)-pyridinones, which are usefulas cardiotonic agents, where R₂ is hydrogen or methyl.

The invention in a process aspect comprises reacting2-(lower-alkanoyl)-1-(lower-alkyl)ethenamine with a lower-alkyl2-propynoate or 2-butynoate to produce5-(lower-alkanoyl)-6-(lower-alkyl)-2(1H)-pyridinone or5-(lower-alkanoyl)-6-(lower-alkyl)-4-methyl-2(1H)-pyridinone.

A composition aspect of the invention resides in a cardiotoniccomposition for increasing cardiac contractility in a patient, saidcomposition comprising a pharmaceutically acceptable carrier and, as theactive ingredient thereof, a cardiotonically effective amount of3-Q-4-R₂ -5-(lower-alkanoyl)-6-(lower-alkyl)-2(1H)-pyridinone, where Qis hydrogen or cyano and R₂ is hydrogen or methyl.

In a method aspect, the invention relates to a method for increasingcardiac contractility in a patient requiring such treatment whichcomprises the administration of a medicament comprising apharmaceutically acceptable carrier and, as the active componentthereof, a cardiotonically effective amount of 3-Q-4-R₂-5-(lower-alkanoyl)-6-(lower-alkyl)-2(1H)-pyridinone, where Q ishydrogen or cyano and R₂ is hydrogen or methyl.

In another process aspect, the invention resides in hydrolyzing 4-R₂-5-(lower-alkanoyl)-6-(lower-alkyl)-1,2-dihydro-2-oxo-nicotinonitrile toproduce the corresponding substituted nicotinic acid and decarboxylatingsaid nicotinic acid to produce 4-R₂-5-(lower-alkanoyl)-6-(lower-alkyl)-2(1H)-pyridinone.

Another composition of matter aspect of the invention resides in6-ethyl-1,2-dihydro-2-oxo-5-(n-propanoyl)-nicotinonitrile.

Another composition of matter aspect of the invention resides in methyl4-acetyl-5-amino-2,4-hexadienoate or acid-addition salt thereof.

DETAILED DESCRIPTION INCLUSIVE OF PREFERRED EMBODIMENTS

In a composition of matter aspect the invention resides in 4-R₂-5-(lower-alkanoyl)-6-(lower-alkyl)-2(1H)-pyridinone having formula I##STR1## where R and R₁ are each lower-alkyl and R₂ is hydrogen ormethyl. The compounds of formula I are useful as cardiotonic agents, asdetermined by standard pharmacological evaluation procedures. Preferredembodiments are those of formula I where R₂ is hydrogen, R₁ is methyl orethyl and R is methyl, ethyl or propyl.

In one process aspect the invention resides in the process whichcomprises reacting 2-(lower-alkanoyl)-1-(lower-alkyl)ethenamine offormula II ##STR2## where R and R₁ are each lower-alkyl, withlower-alkyl 2-propynoate or 2-butynoate to produce the compound offormula I where R₂ is hydrogen or methyl respectively. Preferredembodiments are those using methyl or ethyl 2-propynoate and theethenamine derivative (II) where R is methyl, ethyl or propyl and R₁ ismethyl or ethyl.

A composition aspect of the invention resides in a cardiotoniccomposition for increasing cardiac contractility, said compositioncomprising a pharmaceutically acceptable carrier and, as the activecomponent thereof, a cardiotonically effective amount of 3-Q-4-R₂-5-(lower-alkanoyl)-6-(lower-alkyl)-2(1H)-pyridinone having formula III##STR3## where Q is hydrogen or cyano, R and R₁ are each lower-alkyl andR₂ is hydrogen or methyl. Preferred embodiments are said compounds offormula III where Q is hydrogen, R₂ is hydrogen, R₁ is methyl or ethyland R is methyl, ethyl or propyl and where Q is cyano, R₂ is hydrogenand R₁ and R are each ethyl.

A method aspect of the invention resides in the method for increasingcardiac contractility in a patient requiring such treatment whichcomprises administering orally or parenterally in a solid or liquiddosage form to such patient a cardiotonically effective amount of3-Q-4-R₂ -5-(lower-alkanoyl)-6-(lower-alkyl)-2(1H)-pyridinone of formulaIII where Q is hydrogen or cyano and R₂ is hydrogen or methyl. Preferredembodiments of this method aspect are those using the above-saidcomposition embodiments where Q is hydrogen, R₂ is hydrogen, R₁ ismethyl or ethyl and R is methyl, ethyl or propyl and where Q is cyano,R₂ is hydrogen and R₁ and R are each ethyl.

Another process of the invention resides in the process which compriseshydrolyzing 4-R₂-5-(lower-alkanoyl)-6-(lower-alkyl)-1,2-dihydro-2-oxonicotinonitrile offormula III where Q is cyano or corresponding 4-R₂-5-(lower-alkanoyl)-6-(lower-alkyl)-1,2-dihydro-2-oxonicotinamide toproduce the corresponding 4-R₂-5-(lower-alkanoyl)-6-(lower-alkyl)-1,2-dihydro-2-oxonicotinic acid anddecarboxylating said substituted-nicotinic acid to produce the 4-R₂-5-(lower-alkanoyl)-6-(lower-alkyl)-2(1H)-pyridinone of formula I.Preferred aspects of this process are those using saidsubstituted-nicotinonitrile where R₂ is hydrogen, lower-alkanoyl isacetyl, n-propanoyl or butanoyl and lower-alkyl is methyl or ethyl.

Another composition of matter aspect of the invention resides in6-ethyl-1,2-dihydro-2-oxo-5-(n-propanoyl)-nicotinonitrile, which isuseful as a cardiotonic agent as determined by standard pharmacologicalevaluation procedures.

Another composition of matter aspect of the invention resides in methyl4-acetyl-5-amino-2,4-hexadienoate or acid-addition salt thereof, whichis useful as an intermediate and as a cardiotonic agent as determined bystandard pharmacological evaluation procedures. Its acid-addition saltis prepared by conventional means using a known inorganic or organicacid. Preferred salts for cardiotonic use are pharmaceuticallyacceptable acid-addition salts, e.g., hydrochloride, methanesulfonate,lactate, sulfate or phosphate.

The term "lower-alkyl" as used herein, e.g., as the meaning for R₁ or Rin formula I, means alkyl radicals having from one to four carbon atomswhich can be arranged as straight or branched chains, illustrated bymethyl, ethyl, n-propyl, isopropyl, n-butyl, sec.-butyl, tert.-butyl andisobutyl. Thus, the term "lower-alkanoyl" as used herein is(lower-alkyl)-carbonyl, i.e., ##STR4## as used in each of formulas I, IIand III.

The molecular structures of the compounds of formula I or III or othercomposition of matter aspects of the invention were assigned on thebasis of evidence provided by infrared, nuclear magnetic resonance andmass spectra, and by the correspondence of calculated and found valuesfor the elementary analysis.

The manner of making and using the instant invention will now begenerally described so as to enable a person skilled in the art ofpharmaceutical chemistry to make and use the same.

The preparation of 5-(lower-alkanoyl)-6-(lower-alkyl)-2(1H)-pyridinoneor 5-(lower-alkanoyl)-6-(lower-alkyl)-4-methyl-2(1H)-pyridinone iscarried out by heating at about 100° C. to 150° C.2-(lower-alkanoyl)-1-(lower-alkyl)ethanamine of formula II with alower-alkyl, preferably methyl or ethyl, 2-propynoate or 2-butynoate,respectively, with or without a suitable solvent.

The intermediate 2-(lower-alkanoyl)-1-(lower-alkyl)-ethenamines offormula II are generally known compounds which are prepared byconventional means, as illustrated hereinbelow in the specific exemplarydisclosure.

The 4-R₂-5-(lower-alkanoyl)-6-(lower-alkyl)-1,2-dihydro-2-oxonicotinonitriles offormula III where Q is cyano or corresponding 4-R₂-5-(lower-alkanoyl)-6-(lower-alkyl)-1,2-dihydro-2-oxonicotinamides areconveniently hydrolyzed to produce the correspondinglysubstituted-nicotinic acids under aqueous acidic conditions by heatingwith aqueous mineral acid, preferably sulfuric acid and preferably atabout 70° C. to 130° C. Alternatively, this hydrolysis can be carriedout under aqueous alkaline conditions, preferably using aqueous sodiumor potassium hydroxide at about 95°-100° C.

Decarboxylation of the 4-R₂-5-(lower-alkanoyl)-6-(lower-alkyl)-1,2-dihydro-2-oxonicotinic acids toproduce the corresponding 4-R₂-5-(lower-alkanoyl)-6-(lower-alkyl)-2(1H)-pyridinones of formula I iscarried out by heating in the absence or presence of a suitable inertsolvent at about 240° C. to 280° C., preferably at about 245° C. to 250°C.

The 4-R₂-5-(lower-alkanoyl)-6-(lower-alkyl)-1,2-dihydro-2-oxonicotinonitriles offormula III where Q is cyano or 4-R₂-5-(lower-alkanoyl)-6-(lower-alkyl)-1,2-dihydro-2-oxonicotinamides areprepared by a generally known method (Sunthankar et al., supra) or animproved modification thereof, as illustrated hereinbelow in thespecific exemplary disclosure.

The following examples will further illustrate the invention without,however, limiting it thereto.

A. 5-(LOWER-ALKANOYL)-6-(LOWER-ALKYL)-1,2-DIHYDRO-2-OXONICOTINONITRILES

A-1. 5-Acetyl-1,2-dihydro-6-methyl-2-oxonicotinonitrile--A solutioncontaining 60 g of dimethylformamide dimethyl acetal and 50 g of2,4-pentanedione was heated on a steam bath for 2.5 hours and cooled. Tothe resulting solution containing3-dimethylaminomethylene-2,4-pentanedione was added 300 ml of methanol,27 g of sodium methoxide and 47 g of cyanoacetamide. The resultingmixture was heated on a steam bath for 4 hours, the hot solution pouredinto 700 ml of water and the aqueous mixture acidified with acetic acidand chilled in an ice bath. The solid that separated was collected,dried, and heated with 400 ml. of methanol. Insoluble material wasfiltered from the hot methanol mixture and the filtrate cooled. Theproduct that separated was collected and dried at 90° C. to produce 24.6g of 5-acetyl-1,2-dihydro-6-methyl-2-oxonicotinonitrile, m.p. 227°-230°C. [Sunthankar et al., supra, m.p. 231° C.]

A-2. 6-Ethyl-1,2-dihydro-2-oxo-5-(n-propanoyl)nicotinonitrile--To astirred mixture containing 200 ml of dimethylformamide and 128 g of3,5-heptanedione was added 134 ml of dimethylformamide dimethyl acetalover a 15 minute period and the resulting mixture was allowed to standat room temperature overnight. The reaction mixture was then heated on asteam bath for 1 hour and concentrated on a rotary evaporator to aconstant weight of 186.4 g, as a deep yellow oil, of4-dimethylaminomethylene-3,5-heptanedione. To a stirred mixturecontaining 186.4 g of 4-dimethylaminomethylene-3,5-heptanedione, 92 g ofcyanoacetamide and 1200 ml of methanol was added over a ten minuteperiod 57 g of sodium methoxide, whereupon a mild exothermic reactiontook place. The resulting mixture was refluxed for 2.5 hours, cooled andthe methanol evaporated using a rotary evaporator. To the yellow residuewas added 1 liter of water and 80 ml of glacial acetic acid. Theseparated white solid was collected, washed with water and dried in avacuum oven at 90°-95° C. to yield 161 g of6-ethyl-1,2-dihydro-2-oxo-5-(n-propanoyl)nicotinonitrile, m.p. 243°-245°C. This sample was used in the subsequent hydrolysis step described inExample B-2 to produce the corresponding nicotinic acid derivative. A 12g sample of the nicotinonitrile was recrystallized from ethanol inquantitative yield to give the compound, as fine white needles, m.p.245°-246° C.

A-3. 5-(n-Butanoyl)-1,2-dihydro-2-oxo-6-n-propylnicotinonitrile, m.p.205°-207° C., 25.4 g, was prepared following the procedure described inExample A-2 first using 25 g of 4,6-nonanedione, 25 ml ofdimethylformamide dimethyl acetal and 25 ml of dimethylformamide toyield, as an oil, 41 g of 5-(dimethylaminomethylene-4,6-nonanedionedioneand then refluxing said dione with a mixture containing 14.3 g ofcyanoacetamide, 300 ml of methanol and 9.3 g of sodium methoxide,evaporating the reaction mixture to dryness, dissolving the residue in200 ml of water, acidifying with acetic acid, collecting and drying theproduct, and recrystallizing the 30.4 g of product from isopropylalcohol.

A-4. 1,2-Dihydro-6-methyl-2-oxo-5-(n-propanoyl)nicotinonitrile and5-acetyl-6-ethyl-1,2-dihydro-2-oxonicotinonitrile--A mixture containing34 g of 2,4-hexanedione, 50 ml of dimethylformamide and 40 ml ofdimethylformamide dimethyl acetal was allowed to stand at roomtemperature overnight and then concentrated on a rotary evaporator atsteam bath temperature to yield, as a liquid,3-dimethylaminomethylene-2,4-hexanedione. A mixture containing said3-dimethylaminomethylene-2,4-hexanedione, 300 ml of methanol 25.2 g ofcyanoacetamide and 16.2 g of sodium methoxide was refluxed with stirringfor 3 hours and then concentrated in vacuo to remove the methanol. Theresidue was dissolved in 300 ml of warm water and filtered. The filtratewas acidified with acetic acid and the resulting precipitate wascollected, washed with water, dried in vacuo at 90°-95° C. andrecrystallized from dimethylformamide (75 ml) to yield 7.8 g of1,2-dihydro-6-methyl-2-oxo-5-(n-propanoyl)nicotinonitrile, m.p.265°-268° C. with decomposition the acidic mother liquor wasconcentrated to dryness and digested with hot methanol and cooled. Theseparated solid was dried, 20.2 g, and recrystallized fromdimethylformamide to yield 9.8 g of finely crystalline material, m.p.259°-263° C. with decomposition. The NMR spectral data for this compoundindicated it to be mostly said1,2-dihydro-6-methyl-2-oxo-5-(n-propanoyl)nicotinonitrile. The resultingmother liquors were combined and concentrated on a rotary evaporator andthe resulting residue was recrystallized from ethanol to yield 20.4 g ofsolid, m.p. 220°-226° C. The NMR spectral data for this solid indicatedit to be a 5:4 mixture of said1,2-dihydro-6-methyl-2-oxo-5-(n-propanoyl)nicotinonitrile and5-acetyl-6-ethyl-1,2-dihydro-2-oxonicotinonitrile. Preliminary attemptsto separate the two compounds by fractional crystallization wereunsuccessful; however, the two compounds should be separable.

A-5. 5-Acetyl-1,2-dihydro-6-methyl-2-oxonicotinonitrile and5-acetyl-1,2-dihydro-6-methyl-2-oxonicotinamide--A mixture containing200 g of 2,4-pentanedione and 300 ml of dimethylformamide dimethylacetal was heated under reflux on a steam bath for 5 hours and thenallowed to stand at room temperature overnight. The excess solvent wasdistilled off using a rotary evaporator to a constant weight of 307 g,as an oil, of 3-dimethylaminomethylene-2,4-pentanedione which wascombined with 700 ml of methanol and 168 g of cyanoacetamide followed by108 g of sodium methoxide with stirring and cooling. The reactionmixture was heated under reflux for 7 hours, cooled and treated with 150ml of glacial acetic acid. The separated solid was collected and thefiltrate evaporated to dryness. The residue was treated with 700 ml ofwater and the insoluble material was collected, washed with water anddried. The two solids were combined and refluxed with 1 liter ofmethanol. The insoluble beige solid was collected, washed with hotmethanol and dried in vacuo at 90°-95° C. to yield 55.8 g of5-acetyl-1,2-dihydro-6-methyl-2-oxonicotinamide, m.p. >320° C. Bothfiltrates were concentrated to a volume of about 800 ml and cooled. Theseparated solid was collected and dried in vacuo at 90°-95° C. to yield100 g of 5-acetyl-1,2-dihydro-6-methyl-2-oxonicotinonitrile, m.p.226°-229° C. Further concentration of the mother liquors yielded another44.2 g of 5-acetyl-1,2-dihydro-6-methyl-2-oxonicotinonitrile, m.p.221°-225° C.

A-6. 5-Acetyl-1,2-dihydro-4,6-dimethyl-2-oxonicotinonitrile--It iscontemplated that this compound can be obtained following the proceduredescribed in Example A-1 using in place of dimethylformamide dimethylacetal a molar equivalent quantity of dimethylacetamide dimethyl acetal.

B. 5-(LOWER-ALKANOYL)-6-(LOWER-ALKYL)-1,2-DIHYDRO-2-OXONICOTINIC ACID

B-1. 5-Acetyl-1,2-dihydro-6-methyl-2-oxonicotinic Acid--A mixturecontaining 34 g of 5-acetyl-1,2-dihydro-6-methyl-2-oxonicotinamide, 50ml of concentrated sulfuric acid and 100 ml of water was heated on asteam bath with stirring for 6 hours. The hot reaction solution wasfiltered and to the filtrate was added 50 ml of water. The resultingmixture was allowed to stand at room temperature overnight whereupon theproduct crystallized out. The separated product was collected, washedwith water, dried in a vacuum oven at 90°-95° C. to yield 16.8 g of5-acetyl-1,2-dihydro-6-methyl-2-oxonicotinic acid, m.p. 238°-241° C.This acid was recrystallized from methanol and dried to yield 14.7 g of5-acetyl-1,2-dihydro-6-methyl-2-oxonicotinic acid, m.p. 241°-243° C.

B-2. 6-Ethyl-1,2-dihydro-2-oxo-5-(n-propanoyl)nicotinic Acid--A mixturecontaining 40.8 g of6-ethyl-1,2-dihydro-2-oxo-5-(n-propanoyl)nicotinonitrile, 50 ml ofwater, 75 ml of concentrated sulfuric acid and 200 ml of acetic acid washeated on a steam bath for 8 hours, cooled and concentrated on a rotaryevaporator to remove the acetic acid and water. The remaining mixturewas diluted with 300 ml of water and chilled for 1 hour in an ice bath.The white solid that separated was collected, washed with water anddried in a vacuum oven at 80° C. and recrystallized from isopropylalcohol-ether and dried in a vacuum oven at 90° C. to yield 34.6 g of6-ethyl-1,2-dihydro-2-oxo-5-(n-propanoyl)nicotinic acid, m.p. 180°-182°C.

B-3. 5-(n-Butanoyl)-1,2-dihydro-2-oxo-6-n-propylnicotinic acid, m.p.183°-185° C., 19.4 g, was prepared following the procedure described inExample B-2 using 22 g of5-(n-butanoyl)-1,2-dihydro-2-oxo-6-n-propylnicotinonitrile, 100 ml ofacetic acid, 25 ml of concentrated sulfuric acid and 10 ml of water, aheating period of 75 hours on a steam bath and recrystallization of theproduct from isoproyl alcohol-n-hexane.

B-4. 5-Acetyl-1,2-dihydro-6-methyl-2-oxonicotinic Acid--A mixturecontaining 52.8 g of 5-acetyl-1,2-dihydro-6-methyl-2-oxonicotinonitrile,150 ml of water and 75 ml of concentrated sulfuric acid was heated on asteam bath for 15 hours whereupon no reaction took place. The reactionmixture was then heated in a oil bath at 130°-140° C. for six hoursallowing the water to form by the reaction to evaporate using anair-cooled condenser. The reaction mixture was allowed to stand at roomtemperature overnight whereupon a white crystalline solid separated. Thesolid was collected, washed with water and dried in a vacuum oven at90°-95° C. to yield 49 g of 5-acetyl-1,2-dihydro-6-methyl-2-oxonicotinicacid, m.p. 239°-241° C. To the filtrate was added aqueous ammonia untilthe pH was about 4 and the solid that separated was collected, washedwith water and dried in vacuo at 90°-95° C. to yield another 5.8 g of5-acetyl-1,2-dihydro-6-methyl-2-oxonicotinic acid, m.p. 238°-241° C.

B-5. 5-Acetyl-1,2-dihydro-4,6-dimethyl-2-oxonicotinic Agent--It iscontemplated that this compound can be obtained following the proceduredescribed in Example B-4 but using in place of5-acetyl-1,2-dihydro-6-methyl-2-oxonicotinonitrile a molar equivalentquantity of 5-acetyl-1,2-dihydro-4,6-dimethyl-2-oxonicotinonitrile.

C. 5-(LOWER-ALKANOYL)-6-(LOWER-ALKYL)-2(1H)-PYRIDINONES BYDECARBOXYLATION OF CORRESPONDING NICOTINIC ACIDS

C-1. 5-Acetyl-6-methyl-2(1H)-pyridinone--A 10 g portion of5-acetyl-1,2-dihydro-6-methyl-2-oxonicotinic acid was heated neat in abath of a boiling mixture of diphenyl and diphenyl ether for 40 minutesand the mixture allowed to cool to room temperature. The reactionmixture was dissolved in hot isopropyl alcohol, treated withdecolorizing charcoal and filtered, and the filtrate allowed to stand atroom temperature for several hours. The separated product was collectedand dried at 90°-95° C. to yield 4.3 g of5-acetyl-6-methyl-2-(1H)-pyridinone, m.p. 193°-195° C.

C-2. 6-Ethyl-5-(n-propanoyl)-2(1H)-pyridinone--A 15 g portion of6-ethyl-1,2-dihydro-2-oxo-5-(n-propanoyl)nicotinic acid was heated in anoil bath at 235°-240° C. for 5 hours, cooled and the reaction mixturedissolved in hot ethanol, treated with decolorizing charcoal andfiltered. The filtrate was evaporated in dryness and the residuerecrystallized from isopropyl alcohol to yield 8.2 g of6-ethyl-5-(n-propanoyl)-2(1H)-pyridinone, m.p. 138°-140° C.

C-3. 5-(n-Butanoyl)-6-n-propyl-2(1H)-pyridinone--A 12.5 g portion of5-(n-butanoyl)-1,2-dihydro-2-oxo-6-n-propylnicotinic acid was heated inan oil bath at 240°-245° C. for 3 hours, cooled and the oily residuecrystallized from n-hexane after washing with cold aqueous sodiumbicarbonate solution to yield 3.8 g of5-(n-butanoyl)-6-n-propyl-2(1H)-pyridinone, m.p. 86°-88° C.

C-4. 5-Acetyl-4,6-dimethyl-2(1H)-pyridinone--It is contemplated thatthis compound can be obtained following the procedure described inExample C-1 using in place of5-acetyl-1,2-dihydro-6-methyl-2-oxonicotinic acid a molar equivalentquantity of 5-acetyl-1,2-dihydro-4,6-dimethyl-2-oxonicotinic acid.

D. 5-(LOWER-ALKANOYL)-6-(LOWER-ALKYL)-2(1H)-PYRIDINONES BY DIRECTSYNTHESIS

D-1. 5-Acetyl-6-methyl-2(1H)-pyridinone--A mixture containing 100 g of2,4-pentanedione, 200 ml of ethanol and 60 ml of a concentrated aqueousammonium hydroxide was allowed to stand at room temperature over theweekend (3 days) and then concentrated on a rotary evaporator to yield83 g of 4-amino-3-penten-2-one as an oil. To the stirred oil was added70 ml of methyl 2-propynoate over a 10 minute period and the resultingsolution was stirred at ambient temperature for 30 minutes whereupon avigorous exothermic reaction took place. After the exothermic reactionhad subsided, the reaction mixture was heated on a steam bath for 2.5hours, the reaction mixture was then dissolved in 300 ml of boilingisopropyl alcohol, the solution treated with decolorizing charcoal andfiltered, and the filtrate concentrated on a rotary evaporator to yielda viscuous liquid. To the viscuous liquid was added 300 ml of ether andthe mixture triturated and allowed to stand at room temperatureovernight. The separated solid was collected, washed with ether anddried to yield 84.6 g of material whose NMR spectram indicated it to bethe uncyclized intermediate, methyl 4-acetyl-5-amino-2,4-hexadienoate.[In another run this compound was isolated, recrystallized from methanoland found to melt at 104°-106° C.] The mother liquor from the above wasconcentrated on a rotary evaporator to a constant weight of 45.6 9 ofdark oil. The oil was combined with the uncyclized material anddissolved in 250 ml of dimethylformamide and the resulting mixture wasrefluxed for 4.5 hours. The reaction mixture was allowed to stand atroom temperature overnight whereupon the crystalline product separated.The crystalline precipitate was collected, washed with isopropylalcohol, dried in a vacuum oven at 90°-95° C. to yield 62.5 g of5-acetyl-6-methyl-2(1H)-pyridinone, m.p. 196°-198° C. The mother liquorfrom the above was concentrated to dryness on a rotary evaporator andthe residue dissolved in 100 ml of isopropyl alcohol, the alcoholsolution treated with decolorizing charcoal and filtered and thefiltrate allowed to stand at room temperature overnight. The precipitatethat separated was collected to yield another 15.2 g of5-acetyl-6-methyl-2(1H)-pyridinone, m.p. 194°-196° C.

D-2. 6-Methyl-5-(n-propanoyl)-2(1H)-pyridinone--A mixture containing 25g of 2,4-hexanedione, 100 ml of ethanol and 25 ml of concentratedaqueous ammonium hydroxide was allowed to stand room temperatureovernight and then concentrated on a rotary evaporator to give 21 g, asa pale yellow oil, a mixture containing 4-amino-3-hexen-2-one and5-amino-4-hexen-3-one. To the oil was added 18.5 g of methyl,2-propynoate and the mixture heated in a oil bath at about 100°whereupon a vigorous exothermic reaction took place. After the reactionhad subsided, the reaction mixture was heated in an oil bath at160°-170° C. for 2 hours and then concentrated on a rotary evaporator togive a gummy material. The latter was crystallized from isopropylalcohol-ether to yield 64 g of6-methyl-5-(n-propanoyl)-2(1H)-pyridinone, m.p. 173°-175° C., whosestructure was confirmed by its NMR spectrum. No other product wasisolated from the mother liquor of the above reaction mixture; however,in another run, Example D-4 hereinbelow, a second product, namely6-ethyl-5-acetyl-2(1H)-pyridinone was isolated.

D-3. 5-Acetyl-4,6-dimethyl-2(1H)-pyridinone--A mixture containing 40 gof 2,4-pentanedione, 100 ml of ethanol and 50 ml of concentrated aqueousammonium hyroxide was allowed to stand at room temperature for 6 hoursand then concentrated on a rotary evaporator to yield, as an oil, 35.4 gof 4-amino-3-penten-2-one. The oil was dissolved in 100 ml ofdimethylformamide and to the solution was added 32 g of methyl2-butynoate and the resulting reaction mixture was refluxed for 95 hoursand then concentrated on a rotary evaporator. The remaining oil residuewas heated with 100 ml of ether whereupon a white solid crystallizedspontaneously. The solid was collected, washed with ether and dried in avacuum oven at 90°-95° C. to yield 25.7 g of5-acetyl-4,6-dimethyl-2(1H)-pyridinone, m.p. 160°-162° C.

D-4. 6-Methyl-5-(n-propanoyl)-2(1H)-pyridinone and5-Acetyl-6-ethyl-2(1H)-pyridinone--A mixture containing 50 g of2,4-hexanedione, 100 ml of ethanol and 50 ml of concentrated aqueousammonium hydroxide was allowed to stand at room temperature overnightand then concentrated on a rotary evaporator at 50°-60° C. to a constantweight of 48.8 g, a pale yellow oil that solidified on standing at roomtemperature. The nmr spectrum of this solid in CDCl₃ indicated it to bea mixture of 5-amino-4-hexen-3-one and 4-amino-3-hexen-2-one in a weightratio of 65:35. The mixture of amino-hexen-ones was dissolved in 100 mlof dimethylformamide and treated with methyl 2-propynoate and theresulting mixture was first gently heated with stirring on a steam bathfor 2 hours and then refluxed for 24 hours. The reaction mixture wasallowed to cool to room temperature and allowed to stand at roomtemperature overnight. The crystalline material that separated wascollected, washed with isopropyl alcohol and dried in vacuo at 90°-95°C. to yield 11.9 g of 6-methyl-5-(n-propanoyl)-2(1H)-pyridinone, m.p.173°-175° C. The mother liquor was concentrated on a rotary evaporatorand the residue was crystallized from isopropyl alcohol, washed withether and dried to yield another 10.4 g of6-methyl-5-(n-propanoyl)-2(1H)-pyridinone, m.p. 173°-175° C. Thefiltrate was concentrated in vacuo to yield 57.8 g of an oily residuewhich was chromatographed on silica gel (700 g) using ether as eluant.Evaporation of the ether fractions yielded 22.4 g of the least polarcomponent, an oily material, a middle fraction of 16.4 g, a viscuousgummy oil, and as the most polar component, 7.8 g, a solid which wasrecrystallized from isopropyl alcohol to yield a white amorphous powder,m.p. 140°-145° C., whose nmr spectrum showed it to consist of 90%5-acetyl-6-ethyl-2(1H)-pyridinone. Six further recrystallizations ofthis product resulted in 1.5 g of pure5-acetyl-6-ethyl-2(1H)-pyridinone, m.p. 162°-164° C., as shown by itsnmr spectrum.

D-5. 5-(n-Butanoyl)-6-methyl-2(1H)-pyridinone--A mixture containing 22.2g of 3-methyl-5-n-propylisoxazole [Kashima et al., Bull. Chem. Soc.Japan 46, 310-313 (1973)], 500 mg of platinum dioxide and 200 ml ofethanol was hydrogenated under catalytic hydrogenation conditions forninety minutes, the catalyst was filtered off and the filtrate wasconcentrated on a rotary evaporator to yield 18.5 g of colorless residuewhich solidified on cooling. The residue containing2-amino-2-hepten-4-one was dissolved in 50 ml of dimethylformamide andto the solution was added 14.8 g of methyl 2-propynoate. The resultingreaction solution was allowed to stand at ambient temperature for thirtyminutes (exothermic) and then refluxed for three and one half hours. Thedimethylformamide was removed on a rotary evaporator. The remaining darkbrown liquid was heated in an oil bath at 195°-200° C. for four hours,cooled to room temperature, crystallized from isopropyl alcohol anddried at 80°-85° C. to produce, as pale yellow flakes, 9.4 g of5-(n-butanoyl)-6-methyl-2(1H)-pyridinone, m.p. 167°-168° C.

Following the procedure described in Example D-5 using in place of3-methyl-5-n-propylisoxazole a molar equivalent quantity of theappropriate 3-methyl-5-R-isoxazole, it is contemplated that the5-(RCO)-6-methyl-2(1H)-pyridinones of Examples D-6 and D-7 can beprepared via the appropriate 2-amino-2-alken-4-one.

D-6. 6-Methyl-5-(n-pentanoyl)-2(1H)-pyridinone, first using5-n-butyl-3-methylisoxazole and then 2-amino-2-octen-4-one.

D-7. 6-Methyl-5-(3-methylpropanoyl)-2(1H)-pyridinone, first using5-isopropyl-3-methylisoxazole and then 2-amino-5-methyl-2-hexen-4-one.

The usefulness of the compounds of formula I or III or methyl4-acetyl-5-amino-2,4-hexadienoate as cardiotonic agents is demonstratedby their effectiveness in standard pharmacological test procedures, forexample, in causing a significant increase in contractile force of theisolated cat or guinea pig atria and papillary muscle and/or in causinga significant increase in the cardiac contractile force in theanesthetized dog with lower or minimal changes in heart rate and bloodpressure. Detailed descriptions of these test procedures appear in U.S.Pat. No. 4,072,746, issued Feb. 7, 1980.

When tested by said isolated cat or guinea pig atria and papillarymuscle procedure, the compounds of formula I or III at doses of 1, 10,30 and/or 100 μg/ml., were found to cause significant increases, thatis, greater than 25% (cat) or 30% (g.pig) in papillary muscle force andsignificant increases, that is, greater than 25% (cat) or 30% (g.pig) inright atrial force, while causing a lower percentage increase (aboutone-half or less than the percentage increase in right atrial force orpapillary muscle force) in right atrial rate. Because of the lowercontrol active tensions of guinea pig tissues, the percent change fromcontrol values of both rate and force responses is elevated slightly,i.e., 5%. Thus, whereas cardiotonic activity is ascertained with apapillary muscle force or right atrial force increase of 26% and greaterin the cat test, corresponding activity in the guinea pig test isdesignated with a papillary muscle force or right atrial force increaseof 31% or greater. For example, when tested by said guinea pig atria andpapillary muscle procedure, the following illustrative compounds werefound to cause respective papillary muscle force and right atrial forceincreases as follows: Example D-2, 39% and 35% at 1 μg/ml, 103% and 85%at 3 μg/ml, 120% and 107% at 10 μg/ml; Example C-1, 95% and 66% at 10μg/ml, 109% and 114% at 30 μg/ml and 164% and 229% at 100 μg/ml; ExampleC-2, 77% and 78% at 10 μg/ml, 103% and 132% at 30 μg/ml and 160% and374% at 100 μg/ml; Example D-3, 83% and 56% at 100 μg/ml; Example D-4(5-acetyl-6-ethyl-2(1H)-pyridinone), 86% and 37% at 10 μg/ml and 146%and 40% at 30 μg/ml; Example D-5, 65% and 115% at 1 μg/ml, 92% and 183%at 3 μg/ml and 145% and 237% at 10 μg/ml. Example A-2, 101% and 56% at10 μg/ml, 164% and 111% at 30 μg/ml; Example A-4, 57% and 55% at 30μg/ml and 128% and 146% at 100 μg/ml; Example A-3, 72% and 82% at 30μg/ml and 136% and 131% at 100 μg/ml; and Example A-1, 90% and 41% at 30μg/ml and 82% and 105% at 100 μg/ml. When tested by said guinea pigatria and papillary muscle procedure, methyl4-acetyl-5-amino-2,4-hexadienoate was found to cause papillary muscleforce and right atrial force increases of 55% and 279% respectively at100 μg/ml.

When tested by said anesthetized dog procedure, the compounds of formulaI or III at doses of 0.03, 0.10, 0.30, 1.0 and/or 3.0 mg/kg administeredintravenously were found to cause significant increases, that is, 25% orgreater, in cardiac contractile force or cardiac contractility withlower changes in heart rate and blood pressure. For example, when testedat one or more of said dose levels by this procedure, the compounds ofExamples C-1, C-2, A-2, A-4, D-2, D-4 and D-5 were found to causeincreases of 36% to 218% in contractile force with lower changes inheart rate and blood pressure.

The present invention includes within its scope a cardiotoniccomposition for increasing cardiac contractility, said compositioncomprising a pharmaceutically acceptable carrier and, as the activecomponent thereof, the compound of formula III. The invention alsoincludes within its scope the method for increasing cardiaccontractility in a patient requiring such treatment which comprisesadministering to such patient a cardiotonically effective amount of thecompound of formula III. In clinical practice said compound willnormally be administered orally or parenterally in a wide variety ofdosage forms.

Solid compositions for oral administration include compressed tablets,pills, powders and granules. In such solid compositions, at least one ofthe active compounds is admixed with at least one inert diluent such asstarch, calcium carbonate, sucrose or lactose. These compositions mayalso contain additional substances other than inert diluents, e.g.,lubricating agents, such as magnesium stearate, talc, and the like.

Liquid compositions for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups and elixirscontaining inert diluents commonly used in the art, such as water andliquid paraffin. Besides inert diluents such compositions may alsocontain adjuvants, such as wetting and suspending agents, andsweetening, flavoring, perfuming and preserving agents. According to theinvention, the compounds for oral administration also include capsulesof absorbable material, such as gelatin, containing said activecomponent with or without the addition of diluents or excipients.

Preparations according to the invention for parenteral administrationinclude sterile aqueous, aqueous-organic, and organic solutions,suspensions and emulsions. Examples of organic solvents or suspendingmedia are propylene glycol, polyethylene glycol, vegetable oils such asolive oil and injectable organic ester such as ethyl oleate. Thesecompositions can also contain adjuvants such as stabilizing, preserving,wetting, emulsifying and dispersing agents.

They can be sterilized, for example by filtration through abacterial-retaining filter, by incorporation of sterilizing agents inthe compositions, by irradiation or by heating. They can also bemanufactured in the form of sterile solid compositions which can bedissolved in sterile water or some other sterile injectable mediumimmediately before use.

The percentage of active component in the said composition and methodfor increasing cardiac contractility can be varied to that a suitabledosage is obtained. The dosage administered to a particular patient isvariable, depending upon the clinician's judgement using as thecriteria: the route of administration, the duration of treatment, thesize and condition of the patient, the potency of the active componentand the patient's response thereto. An effective dosage amount of activecomponent can thus only be determined by the clinician considering allcriteria and utilizing his best judgement on the patient's behalf.

We claim:
 1. A 5-(lower-alkanoyl)-6-(lower-alkyl)-2(1H)-pyridinonehaving the formula ##STR5## where R and R₁ are each lower-alkyl.
 2. Acompound according to claim 1 where R₁ is methyl or ethyl and R ismethyl, ethyl or propyl.
 3. 5-Acetyl-6-methyl-2(1H)-pyridinone accordingto claim
 1. 4. 6-Methyl-5-(n-propanoyl)-2(1H)-pyridinone according toclaim
 1. 5. 6-Ethyl-5-(n-propanoyl)-2(1H)-pyridinone according toclaim
 1. 6. 5-Acetyl-6-ethyl-2(1H)-pyridinone according to claim
 1. 7.5-n-Butanoyl-6-methyl-2(1H)-pyridinone according to claim
 1. 8. Acardiotonic composition for increasing cardiac contractility, saidcomposition comprising a pharmaceutically acceptable inert carrier and,as the active component thereof, a cardiotonically effective amount of5-(lower-alkanoyl)-6-(lower-alkyl)-2(1H)pyridinone having the formula##STR6## where R and R₁ are each lower-alkyl.
 9. A composition accordingto claim 8 where the active component is5-acetyl-6-methyl-2(1H)-pyridinone.
 10. A composition according to claim8 where the active component is6-methyl-5-(n-propanoyl)-2(1H)-pyridinone.
 11. A composition accordingto claim 8 where the active component is6-ethyl-5-(n-propanoyl)-2(1H)-pyridinone.
 12. A composition according toclaim 8 where the active component is 5-acetyl-6-ethyl-2(1H)-pyridinone.13. The method for increasing cardiac contractility in a patientrequiring such treatment which comprises administering orally orparenterally in a solid or liquid dosage form to such patient acardiotonic composition comprising a pharmaceutically acceptable inertcarrier and, as the active component thereof, a cardiotonicallyeffective amount of 3-Q-4-R₂-5-(lower-alkanoyl)-6-(lower-alkyl)-2(1H)pyridinone having the formula##STR7## where Q is hydrogen or cyano, R and R₁ are each lower-alkyl andR₂ is hydrogen or methyl.
 14. A method according to claim 13 where theactive component is 5-acetyl-6-methyl-2(1H)-pyridinone.
 15. A methodaccording to claim 13 where the active component is6-methyl-5-(n-propanoyl)-2(1H)-pyridinone.
 16. A method according toclaim 13 where the active component is6-ethyl-5-(n-propanoyl)-2(1H)-pyridinone.
 17. A method according toclaim 13 where the active component is5-acetyl-6-ethyl-2(1H)-pyridinone.
 18. A cardiotonic composition forincreasing cardiac contractility, said composition comprising apharmaceutically acceptable inert carrier and, as the active componentthereof, a cardiotonically effective amount of6-ethyl-1,2-dihydro-2-oxo-5-(n-propanoyl)nicotinonitrile.
 19. The methodfor increasing cardiac contractility in a patient requiring suchtreatment which comprises administering orally or parenterally in asolid or liquid dosage form to such patient a cardiotonically effectiveamount of the active component of claim 18.